Atopic asthma is a chronic inflammatory disorder in which Th2 inflammation plays an important role. Asthma is also a growing health problem whose prevalence has doubled in the last 20 years. The development of asthma is influenced and/or dictated by intrauterine as well as environmental factors that express themselves in early life. However, the environmental factors that are responsible for the increase in asthma prevalence are poorly understood. Recent studies have noted inverse relationships between Tb skin tests and asthma, a lower prevalence of asthma in polluted East as versus clean West Germany and a lower prevalence of asthma in populations with specific early life infections. These studies have led to the following hypothesis. Hypothesis: (1) There are crucial periods of time in utero and/or in early life during which Th1/Th2 polarization alters later life airway responses to asthma-relevant stimuli. (2) During these crucial periods, early life Th1 polarization prevents or diminishes the intensity of later life Th2 responses. We propose to test this hypothesis using a novel, lung-specific, externally regulatable overexpression transgenic system developed in our laboratory which allows genes to be activated in utero, in neonatal or in adult animals. We will: (1) Generate and characterize overexpression transgenic mice in which the airway cytokine milieu can be modified to generate/augment local Th1 responses at different points in time during development. Mice that overexpress IFN-gamma, IL-12 and/or IL-18 will be generated and evaluated. (2) Generate and characterize overexpression transgenic mice in which the airway cytokine milieu can be modified to generate/augment Th2 responses at different points in time during development. Mice that overexpress IL-4 will be generated and evaluated. (3) Characterize the effects of Th1 or Th2 polarization on host response to aeroallergen.